Principal Investigators (Last, first, middle): Wang, Xiaolei & Kaushal, Deepak PROJECT SUMMARY/ABSTRACT: Tuberculosis (TB) is the leading cause of death in Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients worldwide, and this is particularly true for infants. Although studies have disclosed some aspects of pathological changes in HIV/Mtb co-infected adults, very little is known about the pathogenesis and efficacy of therapeutic strategies in HIV-associated Mtb infection in infants, who possess a developing immune system that increases their vulnerability to certain infectious diseases. Recent advances in understanding of neonatal immunity indicate that both innate and adaptive responses are dependent on precursor frequencies of lymphocytes, antigenic dose, and mode of exposure. Clinical course of pediatric HIV has revealed perinatally acquired HIV infection occurs during a critical window of immune development, and HIV's perturbation of this dynamic process may account for the striking age-dependent differences in HIV disease progression. TB in young children is often imperceptible and can rapidly progress to active disease, but the effects of Mtb on the developing immune system of infants is essentially unknown. Therefore, a better understanding of the immunopathogenesis of HIV-associated Mtb infection in pediatric hosts is essential to provide appropriate interventions, which can reduce risk of morbidity and mortality in infants co-infected with HIV and Mtb. We have been using nonhuman primate models to study neonatal immunology and have shown the neonatal immune system is highly compartmentalized, with a much more competent mucosal immune system than the systemic system at birth, and pediatric SIV infection results in impaired development and function of the neonatal mucosal and systemic immune systems. This proposal is designed to determine the immunological changes induced by SIV infection that contributes to the increased severity of Mtb in infants, and the effects of early antiretroviral therapy (ART) and immunotherapy (IDO-inhibitor treatment) on both infections by comparing viral/bacterial burdens, innate, adaptive, and pathogen specific cellular and humoral immune responses, pulmonary pathology, latency, reservoirs, and disease progression. The objectives of our studies are to: a) characterize the effects of Mtb on the development and maturation of systemic and mucosal immune systems in infant macaques that with or without immunotherapy; b) compare immune responses and pathology in SIV/Mtb co-infected infant macaques; and c) determine whether early initiation of ART with subsequent immunotherapy reduces morbidity and mortality among HIV-associated Mtb infection in infants. By using a comprehensive and multipronged approach to define the impacts of Mtb infection on the development and function of the immune system, and identifying mechanisms underlying restoration of Mtb-specific immune function in SIV-infected infants, our studies will advance our understandings of the immunopathogenesis of TB in HIV-infected children, which may provide new insights into immune mechanisms that can be targeted for more effective prevention and treatment strategies for infants co-infected with Mtb. -1-